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Randomized phase II study of FOLFOXIRI plus BEVACIZUMAB plus ATEZOLIZUMAB versus FOLFOXIRI plus BEVACIZUMAB as first-line treatment of unresectable metastatic colorectal cancer patients - AtezoTRIBE

Studio Clinico

Patologia: Tumori del colon retto

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: 

Fase di studio: II Randomizzato

Richiesta mandatoria di tessuto: 

Linee di trattamento: Prima linea

Criteri di inclusione: 

• Written informed consent to study procedures
• Histologically proven diagnosis of colorectal cancer
• Initially unresectable metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease
• At least one measurable lesion according to RECIST1.1 criteria
• Availability of a tumoral sample
• Male or female of 18-75 years of age
• ECOG PS < or = 2 if aged < 71 years, ECOG PS = 0 if aged 71-75 years
• Life expectancy of at least 12 weeks
• Previous adjuvant chemotherapy allowed only if with fluoropyrimidine monotherapy and more than 6 months elapsed between the end of adjuvant and first relapse
• Neutrophils >1.5 x 109/L, Platelets >100 x 109/L, Hgb >9 g/dl
• Total bilirubin 1.5 time the upper-normal limits (UNL) of the normal values and ASAT (SGOT) and/or ALAT (SGPT) <2.5 x UNL (or <5 x UNL in case of liver metastases) alkaline phosphatase <2.5 x UNL (or <5 x UNL in case of liver metastases)
• Creatinine clearance ≥50 mL/min or serum creatinine 1.25 x UNL
• INR or aPTT ≤1.5 × ULN. Patients who are on therapeutic doses of anti-coagulants are eligible if they are on a stable dose of anti-coagulant for 28 days with stable INR and PTT values
• Urine dipstick of proteinuria <2+. Patients discovered to have 2+ proteinuria on dipstick urinalysis at baseline, should undergo a 24-hour urine collection and must demonstrate ≤1 g of protein/24 hr
• Male subjects with female partners of childbearing potential must be willing to use adequate contraception – Contraception, starting with the first dose of study therapy through 6 months after the last dose of bevacizumab and within 5 months after the last dose of atezolizumab.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• Women of childbearing potential must have a negative blood pregnancy test at the baseline visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 continuous months, are surgically sterile, or are sexually inactive.
• Female subjects of childbearing potential must be willing to use an adequate method of contraception – Contraception, for the course of the study starting with the first dose of study therapy through 6 months after the last dose of bevacizumab and within 5 months after the last dose of atezolizumab.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• Will and ability to comply with the protocol

Criteri di esclusione: 

• Radiotherapy to any site within 4 weeks before the study
• Previous adjuvant oxaliplatin-containing chemotherapy
• Previous treatment with bevacizumab
• Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents
• Untreated brain metastases or spinal cord compression or primary brain tumours
• History or evidence upon physical examination of CNS disease unless adequately treated
• Hystory of haemoptysis ≥2 grade NCIC-CTG criteria within one month prior screening
• Active or untreated CNS metastases. Patients with a history of treated asymptomatic CNS metastases are eligible provided they meet all the following criteria:
    - Measurable disease outside the CNS
    - Only supratentorial or cerebellar metastases allowed (i.e. no metastases to midbrain, pons, medulla or spinal cord)
    - No ongoing requirement for corticosteroid therapy for CNS disease
• Symptomatic peripheral neuropathy > 2 grade NCIC-CTG criteria
• Serious, non-healing wound, ulcer, or bone fracture
• Evidence of bleeding diathesis or coagulopathy
• Uncontrolled hypertension and prior histor of hypertensive crisis or hypertensive encephalopathy
• Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication
• Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment.
• Active infection requiring antibiotics at the time of initiation of study treatment
• Any previous venous thromboembolism ≥ NCI CTCAE Grade 4
• History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to the first study treatment.
• Current or recent (within 10 days prior to study treatment start) ongoing treatment with anticoagulants for therapeutic purposes
• Chronic, daily treatment with high-dose aspirin (>325 mg/day)
• Treatment with any investigational drug within 30 days prior to enrollment or 2 investigational agent half-lives (whichever is longer)
• Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to initiation of study treatment
• Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication
• Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception (barriere contraceptive measure or oral contraception) during the study and until 6 months after the last dose of bevacizumab and within 5 months after the last dose of atezolizumab.
• History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis,
Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
    - Note: History of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study.
    - Note: Controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study.
• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan
    - Note: History of radiation pneumonitis in the radiation field (fibrosis) is permitted
• Positive test for human immunodeficiency virus (HIV)
• Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test prior to randomization) or hepatitis C
    - Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible.
    - Note: Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
• Active tuberculosis
• Prior allogenic bone marrow transplantation or solid organ transplant
• Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumour necrosis factor [TNF] agents) within 2 weeks prior to start of study treatment, or requirement for systemic immunosuppressive medications during the trial. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed.
    - Note: Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study.
• Known hypersensitivity or allergy to Chinese hamster ovary cell products or any component of the atezolizumab formulation
• Administration of a live, attenuated vaccine within 4 weeks prior to start of study treatment or anticipation that such a live attenuated vaccine will be required during the study
• Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to start of study treatment
• If receiving a RANKL inhibitor (e.g. denosumab), unwilling to adopt alternative treatment such as (but not limited to) bisphosphonates, while receiving atezolizumab.

Trattamento sperimentale: 

FOLFOXIRI + Bevacizumab + Atezolizumab

Trattamento di controllo: 

FOLFOXIRI + Bevacizumab

Obiettivi primari dello studio: 

Primary objective of this study is to evaluate the efficacy of the addition of atezolizumab to FOLFOXIRI plus bev as first line treatment of patients with metastatic colorectal cancer in terms of Progression Free Survival (PFS).

Obiettivi secondari dello studio: 

Secondary objectives of this study are to assess the safety, activity and efficacy of the addition of atezolizumab to FOLFOXIRI plus bev in terms of:
• Overal toxicity rate
• Toxicity rate
• Objective response rate according to RECIST version 1.1 criteria (ORR)
• Immuno-related objective response rate according to modified RECIST criteria (irORR)
• Early Objective Response Rate (EOR)
• Deepness of response (DoR)
• R0 Resection Rate
• Progression Free Survival 2 (PFS2)
• 2nd-PFS
• Time to failure of strategy (TFS)
• Overall Survival (OS)
• Translational analyses including the evaluation of immunity-related parameters on samples collected both before and after the treatment.

Note generali: 

Al 27-11-2018 l'AOU Pisana - S. Chiara risulta l'unico centro attivo in Italia

Centri partecipanti

Nord Italia

Fondazione Poliambulanza Istituto Ospedaliero
Via Bissolati 57 - 25124 Brescia - BS

Riferimento: Dr. Alberto Zaniboni
Telefono: 0303515553
Email: alberto.zaniboni@poliambulanza.it

 

ASST di Cremona
Viale Concordia 1 - 26100 Cremona - CR
Istituti Ospitalieri

Riferimento: Dr. Gianluca Tomasello

 

Azienda Ospedaliera S. Croce e Carle di Cuneo
Via Michele Coppino 26 - 12100 Cuneo - CN

Riferimento: Dr.ssa Cristina Granetto
Email: granetto.c@ospedale.cuneo.it

 

IRCCS - IRST
Via P. Maroncelli 40 - 47014 Meldola - FC

Riferimento: Dr. Giovanni Luca Frassineti

 

IRCCS A.O.U. San Martino - IST
Largo Rosanna Benzi 10 - 16132 Genova - GE

Riferimento: Dr. Alberto Ballestrero

 

IRCCS Istituto Nazionale dei Tumori
Via Venezian 1 - 20133 Milano - MI

Riferimento: Dr. Filippo Pietrantonio

 

A.O.U. Policlinico di Modena
Via del Pozzo 71 - 41100 Modena - MO

Riferimento: Dr. Gabriele Luppi
Telefono: 0594225646

 

Istituto Oncologico Veneto IRCCS
Via Gattamelata 64 - 35128 Padova - PD

Riferimento: Dr.ssa Sara Lonardi
Telefono: 0498215910
Email: oncologia1@iov.veneto.it

 

Presidio Ospedaliero di Faenza
Viale Stradone 9 - 48018 Faenza - RA

Riferimento: Dr. Stefano Tamberi
Telefono: 0546601193
Email: stefano.tamberi@auslromagna.it

 

IRCCS Candiolo (TO)
St.Provinciale Km 3,95 SP142 - 10060 Candiolo - TO

Riferimento: Francesco Leone
Telefono: 0119933250
Email: francesco.leone@ircc.it

 

AOU Città della Salute e della Scienza di Torino
Corso Bramante 88 - 10126 Torino - TO
AOU S. Giovanni Battista - Molinette

Riferimento: Dr.ssa Patrizia Racca

 

Azienda Ospedaliera Santa Maria della Misericordia
Piazzale Santa Maria della Misericordia 15 - 33100 Udine - UD

Riferimento: Dr.ssa Nicoletta Pella

 

Ospedale di Vicenza
Viale Rodolfi 37 - 36100 Vicenza - VI

Riferimento: Dr. Giuseppe Aprile
Telefono: 0444753259
Email: giuseppe.aprile@aulss8.veneto.it

 

Centro Italia

AOU Careggi
Largo Brambilla 3 - 50134 Firenze - FI

Riferimento: Dr. Lorenzo Antonuzzo
Email: oncmed@aou-careggi.toscana.it

 

Polo Oncologico Provinciale Frosinone
Via A. Fabi - 03100 Frosinone - FR

 

Azienda USL 6 Livorno
Viale Alfieri 36 - 57124 Livorno - LI

Riferimento: Dr. Giacomo Allegrini
Telefono: 0586223189
Email: giacomo.allegrini@ulsnordovest.toscana.it

 

AOU Pisana - Santa Chiara
Via Roma 67 - 56126 Pisa - PI
U.O. Oncologia Medica 2

Riferimento: Dr.ssa Chiara Cremolini
Telefono: 050993841
Email: chiara.cremolini@unipi.it

 

Ospedale Felice Lotti Pontedera
Via Roma 151 - 56025 Pontedera - PI

Riferimento: Dr. Giacomo Allegrini

 

Nuovo Ospedale di Prato
Via Suor Niccolina Infermiera 20 - 59100 Prato - PO

Riferimento: Dr.ssa Samantha Di Donato

 

Fondazione Policlinico A. Gemelli
Largo Agostino Gemelli 8 - 00168 Roma - RM

Riferimento: Dr. Emilio Bria
Email: emilio.bria@policlinicogemelli.it

 

Ospedale San Giovanni Calibita Fatebenefratelli
Via di Ponte Quattro Capi 39 - 00186 Roma - RM

Riferimento: Dr. Corsi
Telefono: 066837700
Email: domenicocristiano.corsi@fbf-isola.it

 

Università Campus Bio-medico
Via Álvaro del Portillo 200 - 00128 Roma - RM

Riferimento: Prof. Giuseppe Tonini
Telefono: 06225411227
Email: g.tonini@unicampus.it

 

Università La Sapienza Policlinico Umberto I
Viale del Policlinico 155 - 00161 Roma - RM

Riferimento: Prof. Enrico
Telefono: 064462982
Email: dhoncologico.cortesi@uniroma1.it

 

Ospedale della Val d'Elsa Senese, Poggibonsi
Località Campostaggia 8 - 53036 Poggibonsi - SI

Riferimento: Dr. Angelo Martignetti
Telefono: 0577994360
Email: angelo.martignetti@uslsudest.toscana.it

 

Sud Italia e isole

Presidio Ospedaliero Garibaldi Nesima
Via Palermo 636 - 95122 Catania - CT

Riferimento: Dr. Roberto Bordonaro
Telefono: 0957595936
Email: oncoct@hotmail.com

 

Ospedale 'Card. G. Panico'
Via San Pio X 4 - 73039 Tricase - LE

Riferimento: Dr. Emiliano Tamburini

 

Azienda Ospedaliera Universitaria Federico II
Via Sergio Pansini 5 - 80131 Napoli - NA

Riferimento: Dr.ssa Chiara Carlomagno

 

Istituto Nazionale Tumori IRCCS Fondazione Pascale
Via Mariano Semmola - 80131 Napoli - NA

Riferimento: Dr. Antonio Avallone
Telefono: 0815903360

 

Seconda Università degli Studi di Napoli
Via L De Crecchio 4 - 80138 Napoli - NA

Riferimento: Prof. Fortunato Ciardiello
Email: Fortunato.CIARDIELLO@unina2.it

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2017-000977-35

Data di inserimento: 27.11.2018

Promotore

Fondazione GONO

CRO

/

Principal Investigator ITALIA

Azienda Ospedaliera Universitaria Pisana - Ospedale S. Chiara

Riferimento: Dr.ssa Chiara Cremolini

Telefono: 050993841

Email: chiara.cremolini@unipi.it

Localita: Pisa

 

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